Benign prostatic hyperplasia (BPH) is typified by epithelial and stromal hyperplasia and progressive enlargement of the prostate gland. BPH is associated with chronic inflammation, however specific mechanisms are unknown. We have reported that hyperplastic BPH epithelium overexpresses interleukin-8 (IL-8) and that this correlated significantly with a myofibroblast reactive stroma phenotype with altered expression patterns of tenascin. IL-8 is a potent chemokine that induces chemotaxis of marrow-derived cells and stimulates reactive stroma / wound repair mechanisms. We have generated a human xenograft model that overexpresses IL-8 and transgenic mouse lines expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and reactive stroma phenotype induced by IL-8(KC) with elevated tenascin-C and pro- collagen I. Our preliminary data suggests that reactive stroma may be recruited from circulating marrow- derived progenitor fibrocyte (CD14+) cells. It is our hypothesis that elevated IL-8 functions to activate and/or recruit reactive stroma progenitor cells at foci of glandular BPH and that this hyperplastic reactive stroma further drives BPH glandular and stromal hyperplasia. To address this hypothesis three Specific Aims are proposed: 1. To characterize the role of IL-8(KC) / CXCR2 signaling and tenascin-C, as a downstream effector, in the induction of prostate hyperplasia. 2. To determine the role of IL-8 / CXCR2 receptor signaling in the recruitment of reactive stroma progenitor cells. 3. To target IL-8(KC) / CXCR2 signaling in reactive stroma cells using drug-inducible gene expression to uncouple signaling and therefore attenuate the genesis of reactive stroma and epithelial hyperplasia in BPH. The purpose of this project is to determine basic mechanisms of IL-8 action in recruiting reactive stroma and establish proof-of-concept that reactive stroma progenitor cells and subsequent reactive stroma can be targeted to uncouple key pathways in order to attenuate the hyperplastic phenotype. PUBLIC HEALTH RELEVANCE: This objective of this study is to determine how interleukin-8 (IL-8) regulates the biology of benign prostatic hyperplasia. This project will provide data on key mechanisms and pathways using several model systems. These mechanisms and pathways may evolve as therapeutic targets.